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Patented July 24, 1951 TUN TED STATES ATE OFFICE.

SPITROTHIOEAREITURIO AoIDs Wilbur J. Doran andEarle Van: l'leyningen, Indianapolis, Ind., assignors to Eli Lilly and Indiana Company, Indianapolis, Ind., a corporation of No Drawing."Application March 119, i949, Serial No. 82485 salts inw'hich R'is a member of the group consisting of "hydrogen and methyl, and R1 and R2 are meme bers of the group consisting of methyl and ethyl; and His hydrogen when both R1 and R2 are ethyl;

and His methyl whenboth R1 andRz are methyl; 25

parenteral administration a water-solublemate iijalis desirable and: hence it is preferable to employ-the compounds 'in the form of their watersomme salts." I I 1' The new acids c'an'beprepared by condensing a 1:1-dicarbethoxycyclopentane with thiourea. The salts can be prepared fromthe corresponding acids by reacting the acid with a suitable base, for example in the case of the potassium salt, by reacting the acid with potassium alcoholate in anhydrous alcohol solution, or with potassium hydroxide in aqueous alcohol solution. Evaporation of the solution of the saltyieldsthe drysaltu f A method ofpreparing the acid compoundsof ou'r iriventionis by the reactions indicated by the acid compounds and their prepal 8 Claims. (01. 260 -260) t following'equations, which R, R1 and R2 have the same significance as hereinbefore and E represents an esterifying radical, for example. a

lo l t'g kl lr t *This is acontinuation-in-part of application S'erialNm 29,958, filed May 28, 1948,. now abandoned q 7 This invention is further illustrated by the following, specific examples.

k 1 v EXAMPLE 1 1 Spiro (2,3,5 trimethylcyclopentane 11,5tthiobarbituric acid) is prepared by the followingsequence oflreactions: I S-methylacetonylacetone .(Yountz andPerkins, 1929, J. AHC. S. .51, 3514), dissolved in absolute ethanol, is reducediwith hydrogen under pressure in the presence of Raney. nickel catalyst. The reactiommixture is filtered, and the filtrate is disstilledl ,Thefraction. boiling at 83-90 C. at a pressurelof about 1.0 mm. of mercury is recovered and consists. essentiallyof;3-methyl-2,5-hexanediol. This'isscooled and saturated with dry hydrogen bromide gas and allowed to stand overnight. It is then resaturated withhydrogen bromide gas and warmed at -60 C. for about '7 hours. The mixture'is then extracted, first with an equal volumeof 48 percent hydrobromic acid solution and then with water, and then is Washed With 10 percent sodium bicarbonate solution. The

7 material is dried with magnesium sulfate, filtered, and distilled. The traction-boiling at -116 C, at a pressure of about 20 mm. of mercury is recovered, and consists essentially of 3-methyl- 2,5i-dibroinohexane.

To 'a solution of 44.6 g. of sodium in 670 cc. of absolutealcohol, 311 g. of ethyl .malonate are and HeyI, 1941, J. A.

added, and the solution is cooled on an ice bath and stirred (which usually causes a precipitate of the sodium derivative of ethyl malonate). To the cool mixture, 251 g. of 3-methyl-2,5-dibromohexane are added rapidly and the mixture is stirred for about an hour without heating. The mixture is then heatedand refluxed for about 2 hours, and then distilled to remove the alcohol. Water is then added, which dissolves the sodium bromide formed in the reaction, and forms a separate layer. The. aqueous layer is separated from the oily organic layer and extracted twice with benzene, and the benzene extracts are added to the organic layer. The: combined organic mix-- ture is dried with magnesium sulfate and distilled. The fraction boiling at M -108 C. at a pressure of about 3 mm. of mercuryis recovered,

and consists essentially of the 1,1-dicarbethoxy- 2,3,5-trimethylcyclopentane;

To a solution of 62 g. of thiourea and 38 g. of

7 sodium in 495 cc. of absolute methanol, are added 141g. of 1,1-dicarbethoxye2,3,5-trimethylcyclo-; The resulting mixture isrefiuxedfor The precipitate is recovered by filtration,

Washed with Water, and crystallized three times from dilute alcohol.

Spiro(2,3,5 trimethylcyclopentane 1,5 thiobarbituriczacid) thus-prepared melted at I, about 15i5 1!77C.: Analysis showed the presence of about 11.54 percentnitrogenas compared with the. calculated: amount of, 11.67 percentnitrogen.

EXAMPLE? The sodium salt of spiro(2,3,5-trimethylcyclopentane-1,-' -thiobarbituric acid) is. prepared} as follows: v

A solution of 33 g; 'of therspirobarbituricaacid inlOll cc. of =absolute-ialcoholis treated with a sufficient amount of solution of' dilute sodium ethylate in ethanol tosbring the solution to' about pH 11. The :solution. is :filtered, the filtrate is evaporated to dryness, and the residue thoroughly driedunder vacuum at about 80. C. for several hours; The-dry material is the desiredisodium salt of spiro(2,3,5 trimethylcyclopentane-1,5'-

. thiobarbituricacid') and is represented by the l l o. /cs. HFCQ CON CH3 Na EXAMPLE 3 Spiro (2. ethyl- 3,5 -dimethylcycl'opentane-1,5 thiobarbituric acid) is prepared.v as follows: I

400 g. of a-allyldiethyl ketone (Cope, Hoyle,

4 a mixture of 375 g. of aluminum isopropoxide' and 2000 cc. of isopropanol.

column for about 11 hours.v Most of theremaim ing isopropanol is then distilled off, and the residue is cooled and acidified with dilutesulfuric acid while maintaining the temperature below 40 C. The mixture now forms two layers, which are separated; The, oily layer is washed with Water and dried, aswith magnesium sulfate, and v I is then-distilled. The fractionboiling at.-92-100 C; at 'a pressure of i58-60 mm: of mercury is recovered, and consists essentially of d-methyl-l-hep tene-5-ol.

This is converted to Q-methyl-Zj-dibromohep 'tane as follows: To 390 g.'of 4-methyl-l-heptene-5-ol areadded cc. of glacial acetic acid,

and the water layer is discarded. The other layer is. Washed with water and with. sodium bicarbonate. solution, and then driedfwith anhydrous potassium carbonate. The dried material is filtered,,. and fractionally. distilled. The fraction boilingat 90'100 C. at apressureof 36 mm. of mercury. is recoveredgandconsists essentially, of 4emethyl-2,5 dibromoheptane.

To. atsolution of 50 g. of sodium in 750 cc. of

absolutealcohol, 346- g. of ethyLmalonate. are

added',-- and the. mixture. cooledand stirred... To

this mixture, 294 g. of 4-methyl-2,5"-dibromoheptane are added andtheresulting mixture is stirred for about 2. hours-without external heating. The mixture is then heated and refluxed, with continued stirring, for about fi hours, and is then distilled to remove the'alcohol. added to the residue. to dissolve "sodium bromide formed in the reaction. The aqueous solution forms a separatelayer which is separated and ex- Toa'solutionof 16.3-ig. of sodium and 27g; of thiourea in 21000. of absolute methanol are added 63.6 g. of 1,l dicarbetlioxy-2 ethyl-3,5-dimethyl cyclopentane; and. ,the .mixture is. refluxed-for about 6"l1ours. Themethanol is. distilled oif, and

the residue cooled and'dissolvled. in water, The

aqueoussolution is: extractedfltwice Withether. to V 1 remove anyunreacted ester and. filtered. The

filtrate is. neutralized with dilute hydrochloric acid. whereupon?a'precipitate of spiro( 2'-et hyl-] 3,5 d'imethylcyclopentane 1-,5' thiobarbituric acid) forms. The thiobarbituric acidis representedebythe.followingformula,

'CHs-r 01H:

H-'H C0=NH l 1 .9 nlo Oil-N tion, treating the solution with decolorizingcar- C. S. 63,1850) are added-to bon, filtering-off themarbonand reprecipitating The mixture is subjected to slow distillation through a fractionating Water is.

accuses:

the-athi'obarbituric acid by the addition. of solid The thiobarbituric acid is ill-- ethanol solution treated with an: equal volume of 'Water and cooled to about C. -Thethiobar bituric acid separates in substantially pure, crys talline-form. It is filtered off and dried.

Spiro(-2 ethyl 3,5 --.dimethylcyclopentane- 1-,5'-'thiobarbituric acid) thus prepared meltedat about 180-18? 0. Analysis showed the presence n1 11111- percent nitrogen as compared with the calculated value of 11.02 percent nitrogen.

Preparation my the sodium salt of spir0(2-ethyl .l3,5-dimethylcyclopentane 1,5 thiobarbituric "A" suspension bf spiro(2-ethyl-3,5-dimethylc yclopentane- 1,5-thiobarbituric acid) in alcohol is treatedwitha su'flicient amount of a solution of ssaium ethylate in alcohol to bring'the mixture to about pH 11. The mixture is then filtered;

the'filtrate evaporated to remove the alcohol; and 18 residue dried under vacuumat about 80 C. forseveral hours. The dryrnaterial is the des'ir'ed lsodium salt of spiro(2-ethyl-3,5-dimethylcyclopentane- Lt'i'-thiobarbituric acid) which is represented by thefollowing formula CH; .CzHs 1 1 H3 1L8. EXAMPLE 5 dimethyl 5 ethylcyclopentane 1,5-. thiobarbituric acid) represented by the formula:

. on, CH3

H OO-NH o os prepared by generally the same series of reactionsdescribed inExample 3 for the preparation of 'spiro(2-ethy1 3,5 dimethylcyclopentane-1,5- thi obarbituric acid), employing the sequential preparation of (l-methylallyl)-acetonitrile by condensation of 1-methylallyl chloride and acetonitrile in liquid ammonia with sodamide, reaction with ethylmagnesium bromide to form 5- methyI-G-heptene-B-Qne, reduction of the ketone with aluminum isopropoxide to form the corresponding alcohol, treatment with hydrogen bro- S piro(2,5 diethylcyclopentane 1, 5thiobarturic acid) is prepared by the following sequence of reactions:

"Acetylene dimagnesium bromide is prepared by passing: acetylene into 3 mols of ethylmagnesium bromide in 1500 cc. of ether until the reaction is complete. The mixture is allowed to stand for several hours and to it are added drop.- wise and with stirring 3 mols (174 g.) of propionaldehyde. 'After theladdition is complete the re action mixture is stirred for about one-half hourat room temperature and is then poured'into a mixture of dilute sulfuric acid and ice water. 4-octyne-3,6-diol separates as a supernatant oily layer. The oily layer is separated and the aqueous layer is extracted four times with ether to recover: the 4-octyne-3,6-diol dissolved therein. The. ether extracts are added tothe 4-octyne3,6-diol and the mixture is washed with sodium carbonate solution and driedwith magnesium sulfate. The ether is removed by evaporation and the residue comprising 4-octyne-3,6-diol is purified by distillation in vacuo. The 4-octyne-3,6-diol boils at -95 C. at a pressure of about 1.0 mm. of mercury. i

41 g. of 4-octyne-3,6-diol are dissolved-in-200 cc. of percent ethanol and 0.5g. of platinum oxide are added. The mixture is hydrogenatedwith hydrogen at about 60- pounds pressure in an and the "residue comprising octane-3;.6-diobis purified bydistillation. Octane-3,6-diol boils at 101-102 C. at a pressure of about 3 mm. of mercury.

62 g. of octane-3,6-diol are dissolved in a mixture of 70 cc. of ether and 5 cc. of glacial acetic acid. The reaction mixture is refluxed and dry hydrogen bromide gas is passed into the refluxing mixture for about eight hours, during which time most of the ether evaporates from the mixture. The reaction mixture'is allowed'to stand at-roomtemperature for aboutlZ hours and the aqueous layer which forms below the organic layer is separated and discarded; The organic layer is heated to about C. and treated with dry hydrogen bromide gasfor about 8 hours. The reaction mixture is allowed to stand for about 10 hours during which time a further quantity of aqueous carbonate solution,and treated with anhydrous.

potassium carbonate. The organic liquid com% prising 3,6-dibromooctane is purified by distilla tion; 3,6-dibromooctane boils at about 63-70 C at apressure of about 1 mm. of mercury. l

l6 g.of sodium are-dissolvedin 240 00-01 absolute ethanol and to the solution are addedllO g. of ethyl malonate. The mixture is cooled and to the cool mixture are added 92.5 g. of 3,6-dibromooctane and the mixture is stirred and refluxed for about 5 hours. The ethanol is distilled from the mixture and the residue treated with water and the aqueous layer containing dissolved sodium bromide is separated and discarded. The organic layer comprising 1,1-dicarbeth.oxy-2,5- diethylcyclopentane is purified by distillation. 1,1- dicarbethoxy-2,5-diethylcyclopentane boils at about 85-87" C. at a pressure of about 1 mm. of mercury. l

48 g. of 1,1-dicarbethoxy-2,5-diethylcyclopentane are added to a solution of 12.4 g. of. sodium in cc. of absolute methanol. 20 .5 g. of thiourea areadded to the solution and the mixture is refluxed for about 7 hours. The methanol is removed by evaporation and the residue containing. spiro- (2,5-diethylcyclopentane4,5 -thiobarbituric acid) as its sodium salt is dissolvedin awanesa:

material and the} ether "extracts. discarded-.1 The; solution :isacidified with. dilute hydrochloric-acid;

whereupon spiro.(2,5 diethylcyclopentane-1,5

thiobarbituric) acid precipitates. Thexthiobarbi-z turic: acid is filtered offliwashedvwith water-and: purified by repeated...recrystillization. from bene zene. Spiroi2,5-diethylcyclopentanedj-thiobarbituric acid) .issrcpresentedbytheiollowing; A

. 1 9 A Spiro(2,5. 5 diethylcyclopentane-1,5-thiobarbi-- turic) acid thus prepared meltsattabout162-164";

C. Analysisshowedrthe presence of 11.02 percent, nitrogenv as com'paredwith thecalculatedvalueof 11.;091: percentnitrogem v EXAMPLE 7 d The; sodium 7 salt. of spiro (2,5.-cliethylcyclope n-.

- tame-1,5sthiobarbituric acid) isobtained'by the barbituric acid) is prepared by the following se- -l quence of reactions. l

Sodium amide is1preparedf by reacting 138 g; of

metallic sodium; with 6 liters of liquid ammonia. To the mixture are added slowly 246 g. ofacetonitrile andthe mixture is'stirred for IOminutes.

To the vigorously stirred mixture are addedas; rapidly as possible, 726 g. oiallylbromide. The

ammonia is evaporated and to the solid residue are added 1500 cc. of water andthe mixtureis i filtered. The filtrate which'comprises an organic layer= containing allylacetonitrile. is separated from the aqueous layer and theaqueous layer is extracted several times with ether to recover the allylacetonitrile dissolved therein. The ether extracts are added to the already separated allylacetonitrile, the mixture is dried with anhydrous magnesium sulfate, and the ether evaporated. The residue'comprisin'g allylacetonitrile is purifled by'distillation. It boils at about l42-15'O C.

To 700 :cc. of diisopropylether'solution of ethyl magnesiumbromide prepared from 48.6 g. of'

magnesium and218 g. ofethylbrcmide'areadded 81" g. of allylacetonitrile dissolved in 250' cc. of absolute diisopropyl ether; The mixture refiuxed for about Zhours'andallowed to standat room temperature for about 8 hours. Thereaction mixture is poured'into ail-mixture of dilute hydrochloric acid and ice, and theethereal' layer which separates is recovered. The aqueous layer" isextracted severaltimesvvith benzene and the extracts added to the ethereal solution-originally recovered; The solutionwhich contains l-hep-' tene S-on'e is dried over magnesium sulfate-and the solvent evaporatedi The residual "1 --heptene'- 5-one is purifiedgby distillation It boilszat' about? 142C. 104 g of: l-heptene-fi-one dissolved in; .350 cc; of.'anhydrousisopropano1 are treated with 1101s,. of; aluminum isopropoxide. Whenthe reactionzise complete the isopropanol is distilled off and the:

residue ispoured into 500 cc. of cold 6' N sulfuric.

acid: An organic layer comprising l-heptene- 5-,0lappearsand is separated. The aqueouslayer isextracted several times with ether to recover. the; 1'-heptene.-. 0l dissolved therein. The. ethe real 'extractsare addedto the lheptene fiaol and, the mixture is washed. withdilute sodium bicarbonate solution and Water until the washings are neutral; The-ether: solution dried with: anhy-- drous magnesium. sulfate; the ether evaporated and the residual l-heptene-5-ol purified bydistillation. It boils at 93-94; C. at a pressureof about'731lmm. of mercury. A'mixture of 791g. of l-heptene-5-0l, 0.5 g; if diphenyl amine, 1042c. of glacial'aceticacld andfiicc. of distilled water is treated with' 113 "'g; of anhydrous hydrogenbromide gas; The mixtureis' allowed to stand atroomitemperature'for about 24 hours and is then heated for about one half "hour and: cooled. The mixture separates intotwo'layersthe upper organic layer contain-" ing- 2,5-dibromo heptane. The organic layer is separated and the aqueous layer is heated for about 30 minutes and cooled and an additional refluxed with stirring foruabout 2 hours, and allowed to cool. Most of the alcohol is distilled oif and to the residue is added '1 liter of water.

1,1 dicarbethoxy-zemethylr 5 ethylcyclopentane appears asanoily layer. The oily layer is 'separated and. theaqueous layer extracted several.

I timeswith ether to recover any l,1-dicarbethoxy-:

2-methyl 5-ethylcyclopentane dissolved: therein. Theether extracts are combined with the. diester already recovered, and the mixture is dried-over magnesium sulfate. The ctheris evaporatedofi andthe residue comprising 1,l-dicarbethoxy -2.- methyl-5-ethylcyclopentane is purified by disti1- laticn. Itboils at 88-91 C. at a-pressure of 0.2 mm.- of, mercury.

103.2 g. of 1,1edicarbethoxy-2emethyl-fi-ethylr' cyclopentane are added to a solution of 46 g. of

thiourea in sodium methylate solution prepared y from 27.9 g. of sodium and 350 cc. of absolute methanol. The solution .is stirred. and-refluxed for about. '6: hours.

in about 500 'cc. of. Water,and thesolution extracted several timeswith ether to remove any unreac-ted ester: The solutionis then acidified with hydrochloric acid: Spiro (2-methyl'-5 ethyl'-* cyclopentane-1,5-thiobarbituric. acid) precipitates as a solid andis filtered'ofi. 'Thethiobarbituric' acid is purified by; dissolving it in dilute sodium hydroxide;- treatin'g'the' solution with de The mixture is stirred'for about 1 hour and is then The methanol is: removed." by distillation and'the residue whichzcontainsz' spiro(2 methyl 5; ethyllcyclopentane 1,5 thiobarbituric acid), as itssodium saltis dissolved colorizing carbon and reprecipitating the thiobarbituric acid by adding an excess of solid carbon dioxide to neutralize the solution. The thiobarbituric acid which precipitates is further purified by recrystallization from dilute ethanol. Spiro (2-methyl-5-ethylcyclopentane 1,5 thio barbituric acid) is represented by the following formula CH5 GHQ-(EH (JO-NH cs oH2-o GON Spiro(2-methyl-5-ethy1cyclopentane-1,5'-thiobarbiturie acid) thus prepared melts at about 172173 0. Analysis has shown the presence of 11.49 percent nitrogen as compared with the calculated value of 11.66 percent nitrogen.

EXAMPLE 9 The sodium salt of spiro(2-methyl-5-ethylcyclopentane-1,5'-thiobarbituric acid) is prepared by the procedure described in Examples 2 and 4. The sodium salt is represented by the formula I 02115 No.

We claim as our invention:

'1. A member of the group consisting of the spiro-thiobarbituric acids and salts thereof represented by the formula 10 3. A member of the group consisting of spire (2 methyl 5 ethylcyclopentanedfi'-thiobarbituric acid) represented by the formula E OH2CH CO-NH /0s CHQr-C \OONH Es v and its alkali metal salts.

4. The sodium salt of spiro(2-methyl-5-ethylcyclopentane-1,5'-thiobarbituric acid) represented by the formula CH2- H OONH 5. Spiro(2,5 diethylcyclopentane 1,5 thiobarbituric acid) represented by the formula os om0 o o-rrfi 2H5 6. Spiro(2 methyl-5-ethylcyc1opentane-1,5- thiobarbituric acid) represented by the formula OH,- H CONH 0s GHQ-C oo-N 2115 '7. The sodium salt of spiro(2-ethyl-3,5-dimethylcyclopentane 1,5 thiobarbituric acid) represented by the formula H3 Na 8. Spiro(2-ethyl 3,5 dimethylcyclopentanel,5-thiobarbituric acid) represented by the formula WILBUR J. DORAN. EARLE M. VAN HEYNINGEN.

No references cited. 

1. A MEMBER OF THE GROUP CONSISTING OF THE SPIRO-THIOBARBITURIC ACIDS AND SALTS THEREOF REPRESENTED BY THE FORMULA 